The effects of DNA intercalating agents and epipodophyllotoxins are being studied. These drugs produce protein-associated DNA strand breaks in mammalian cells and isolated nuclei. The activity responsible for this effect was isolated from cell nuclei and was identified as topoisomerase II. The drugs tend to trap DNA-topoisomerase II complexes in a state in which the enzyme is covalently linked to DNA. This effect is stimulated by the intercalating agents: amsacrine (m-AMSA), 5-iminodaunorubicin, 9-hydroxy-2-methylellipticinium, ellipticine and adriamycin; and by the epipodophyllotoxins: etoposide and teniposide. The methylellipticinium derivative also inhibits this reaction at high concentrations. All of the drugs inhibit the ATP-dependent strand-passage reaction of the enzyme. The genomic localization and regulatory functions of topoisomerase II are under study.